A dynamic 3‐factor survival model for acute myeloid leukemia that accounts for response to induction chemotherapy

Abstract

The current study was approached with the assumption that response to induction chemotherapy, in acute myeloid leukemia (AML), overshadows pre-treatment risk variables in predicting survival and therefore be used as an anchor for a simplified risk model. We considered 759 intensively-treated patients with AML, not promyelocytic: median age 60 years; primary 66%, secondary 25%, and therapy-related 9%; European LeukemiaNet cytogenetic risk category favorable 8%, intermediate 61%, and adverse 31%. Complete remission with (CR) or without (CRi) count recovery was achieved in 608 (80%) patients. After a median follow-up of 22 months, 503 deaths, 272 relapses, and 257 allogeneic hematopoietic stem cell transplants (AHSCTs) were recorded. Multivariable analysis identified failure to achieve CR/CRi (HR 3.8, 95% CI 3.1-4.8), adverse karyotype (2.2, 1.8-2.8), and age >55 years (2.1, 1.6-2.7) as main risk factors for survival. HR-weighted scoring resulted in four-tiered risk stratification: low (0 points; N = 183), intermediate-1 (1 point; N = 331), intermediate-2(2 points; N = 117), and high (≥3 points; N = 128), with respective median survival (5-year rate) not reached (68%), 34 (37%), 13 (20%), and 5 (5%) months (p < .001).FLT3-ITD mutation was associated with inferior survival in intermediate-1 (p = .004) and TP53 in intermediate-2 (p = .06) and high (p = .02) risk disease; the latter was fully accounted for by the close association between TP53 mutation and complex/ monosomal karyotype while the observations regarding FLT3-ITD were not affected by treatment with midostaurin. AHSCT had a favorable impact on survival, most apparent in intermediate-1 (p < .001), intermediate-2 (p = .03), and high (p = .01) risk disease. The proposed 3-factor survival model offers a novel prototype that is amenable to further enhancement by molecular information and was validated in an external cohort of 1032 intensively-treated AML patients.

Prediction of survival with lower intensity therapy among older patients with acute myeloid leukemia

“…In a previous analysis of intensive chemotherapy, the prediction of mutational studies was reduced to only three mutations that remained important: NPM1 (favorable), TP53 , and PTPN11 (both unfavorable) 46 . Similar findings were reported by Tefferi and colleagues 82 who found only FLT3 mutations and NPM1 mutations to matter. In this analysis of lower intensity therapy in older AML, we identified similar mutations to be important: IDH2 and NPM1 (favorable) and TP53 (unfavorable).…”

Acute myeloid leukemia risk models: Where do we stand?

“…In this issue of the American Journal of Hematology Tefferi et al 1 report on a dynamic 3‐factor survival model based on the assumption that response to induction chemotherapy in acute myeloid leukemia (AML) overshadows pre‐treatment risk variables in predicting survival, being therefore adaptable as an anchor for a simplified risk model. The study was conducted on 759 intensively‐treated AML patients and complete remission (CR + CRi) was achieved in 80% of cases.…”

“…In contrast, FLT3 mutations did not emerge as an adverse risk, probably because the patients were frequently referred to allo‐HSCT after intensive chemotherapy and to FLT3 inhibitors. This 12‐factor model is entirely based on pre‐treatment variables and therefore differs from the simpler 3‐factor model by Tefferi et al 1 which includes a critical post‐treatment variable (i.e., response to induction chemotherapy) that might have lessened the impact of certain pre‐treatment variables.…”

“…While the incorporation of the pre‐treatment clinical and molecular data sets is likely to improve prognostic accuracy, information obtained post‐therapy should be also considered important. The study by Tefferi et al 1 has the merit to highlight the value of post‐treatment variables, such as response to induction chemotherapy, in predicting survival in AML. In this regard, it should be noted that CR/CRi is a morphologic definition whose value as a prognostic marker might be further improved by introducing the concept of depth of response (i.e., molecular remission) and assessment of measurable residual disease (MRD) at certain time points during treatment.…”

Therapeutic Advances in Immunotherapies for Hematological Malignancies

“…Recently, novel therapeutic regimens were developed with the combination of intensive chemotherapy with a target agent and lower-intensity therapy to prevent progression or relapse [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. The assessment of next generation sequencing [ 9 , 10 , 11 , 12 , 13 , 14 ], transcriptomic analysis [ 15 , 16 , 17 , 18 ], ultra-accurate duplex sequencing [ 19 ], optical genome mapping [ 20 ], and measurable residual diseases [ 21 , 22 , 23 ] enhanced the accuracy of prediction for prognosis [ 24 , 25 ]. However, survival still remains poor even with progress in supportive therapy [ 26 , 27 , 28 ].…”